Environmental exposure to certain metals has been correlated with increased cancer incidence. Most carcinogens or their metabolites have been shown to be mutagenic. This has not been the case for carcinogenic metals. This proposal seeks to unravel the mechanism of metal mutagenesis and to determine whether some metals might also act as co-mutagens. These studies will involve a comparison of the effects of metals on prokaryotic and eukaryotic systems. Carcinogenic and non-carcinogenic metals will be analyzed in these two systems for toxicity, ability to cause mutations, and ability to interfere with DNA repair or otherwise act as comutagens. It is one of the assumptions of this proposal that existing tester strains of bacteria are inadequate for metal mutagenesis because they have been developed to test mutagenesis by agents which cause bulky lesions on DNA. The process of analyzing the mechanism of metal mutagenesis (which may be fundamentally different from the mechanism of most organic compounds) will involve utilization of E. Coli mutants with a variety of DNA repair deficiencies. Some of these mutants should be more sensitive to metal mutagenesis, and could then be added to the existing stock of tester strains to screen for other agents which are mutagenic by mechanisms similar to those of metals.